MX2010003396A - Orally bioavailable lipid-based constructs. - Google Patents

Abstract

The present invention is embodied by a composition capable of chaperoning a typically non-orally available therapeutic or diagnostic agent through the environment of the digestive tract such that the therapetucic or diagnostic agent is bioavailable. The composition may or may not be targeted to specific cellular receptors, such as hepatocytes. Therapeutic agents include, but are not limited to, insulin, calcitonin, serotonin, and other proteins. Targeting is accomplished with biotin or metal based targeting agents.

Description

ORALALLY AVAILABLE CONSTRUCTIONS BASED ON LIPIDS BACKGROUND OF THE INVENTION One of the most preferred ways of delivering a pharmaceutical product to a subject is in an oral formulation. However, oral formulations of many pharmaceutical compounds are often not available due to the incompatibility of the pharmaceutical product with the aggressive environment of the digestive tract. This applies particularly for pharmaceutical compounds such as peptides, proteins, certain small molecules, and nucleic acids. An oral formulation of a protein such as insulin would be highly desirable. The present strategies to normalize blood glucose levels in Type I and Type II diabetic patients utilize subcutaneous administration of insulin in various time-release formulations, such as ultrafluid Nf insulin and humulin. The use of these formulations retards and subsequently controls the bio-distribution of insulin by regulating the release of the drug to the tissues. Sustained insulin management leads to better glucose control and the need for fewer injections over the course of the disease. Unfortunately, multiple painful injections are still required because these formulations do not provide sustained levels of insulin in the subject suffering from diabetes.

Many other important drugs are also not currently available in oral formulations. Examples include calcitonin, serotonin, parathyroid hormone, GLP-1, erythropoietin, interferon of various types, human growth hormone, monoclonal antibodies, and many others, whose utilities have been extensively reviewed in the literature. What is needed in the oral drug delivery field is a composition that allows oral delivery of a wide variety of pharmaceuticals and other therapeutic agents. The present invention meets and addresses this need.

BRIEF DESCRIPTION OF THE INVENTION The present invention includes compositions that facilitate and / or allow the absorption of therapeutics which are not usually orally bioavailable. In one embodiment, a composition of the invention functions by association with a therapeutic agent and accompanying the therapeutic agent through the lumen of the intestine to the portal blood flow and finally into the systemic circulation. In certain embodiments, the composition of the invention possesses many unique and advantageous properties. One of these properties is the ability to insert into intercellular spaces and cross the mammalian intestine into the portal circulation. In certain embodiments, a composition of the invention it can be directed to specific cellular or extra-cellular receptors through one or more targeting agents. In a typical embodiment, an orally bioavailable composition of the invention comprises gelatin and additional constituents. Additional constituents comprise a dynamically sized liposome, liposome fragment, and lipid particle, wherein the lipid particle comprises at least one lipid component and the liposome or liposome fragment comprises at least two lipid components. The composition further comprises at least one therapeutic or diagnostic agent, and optionally at least one targeting agent. Gelatin actively interacts reversibly with one or more of the constituents in the composition of the invention. In certain embodiments, the lipid components are selected from the group consisting of MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1-2. dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-di-stearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1, 2- dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (succinyl), 1,2-dipalmitoyl- sn-glycero-3- [phospho-rac- (1-glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2- (5 - ((3aS, 6aR) -2-oxohexahydro-1 H-thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl phosphate. In certain embodiments, the therapeutic agent is selected from the group consisting of insulin, interferon, erythropoietin, hormone parathyroid, calcitonin, serotonin, rituximab, trastuzumab, uricase, activator tissue plasminogen, thymoglobin, a vaccine, heparin or an analogue of heparin, anitrombin III, filgrastin, pramilitide acetate, exanatide, epifibatide, antivenins, IgG, IgM, HGH, thyroxine, GLP-1, Factors VII and VIII of blood coagulation, a monoclonal antibody, and glycolipids that act as therapeutic agents.

In a preferred embodiment, the therapeutic agent is insulin. \ In certain modalities, the addressing agent comprises a targeting agent derived from metal or an agent of address derived from biotin.

In a sub-modality, the derived addressing agent metal comprises a metal and at least one forming agent complex. Preferably, the metal in the targeting agent metal derivative is selected from the group consisting of a metal of transition, an inner transition metal and a transition metal neighbor, and; The at least one complexing agent is selected from the group consisting of: N- (2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid; N- (2,6-diethylphenylcarbamoylmethyl) iminodiacetic acid; N- (2,6-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (4-isopropylphenylcarbamoylmethyl) iminodiacetic acid; N- (4-butylphenylcarbamoylmethyl) iminodiacetic acid; N- (2,3-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (2,4-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (2,5-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (3,4-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (3,5-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (3-butylphenylcarbamoylmethyl) iminodiacetic acid; N- (2-butylphenylcarbamoylmethyl) iminodiacetic acid; N- (4-butylphenylcarbamoylmethyl tertiary) iminodiacetic acid; N- (3-butoxyphenylcarbamoylmethyl) iminodiacetic acid; N- (2-hexyloxyphenylcarbamoylmethyl) iminodiacetic acid; N- (4-hexyloxyphenylcarbamoylmethyl) iminodiacetic acid; aminopyrrole iminodiacetic acid; N- (3-bromo-2,4,6-trimethylphenylcarbamoylmethyl) iminodiacetic acid; benzimidazolmethyl iminodiacetic acid; N- (3-cyano-4,5-dimethyl-2-pyrrilcarbamoylmethyl) iminodiacetic acid; N- (3-cyano-4-methyl-5-benzyl-2-pyrrilcarbamoylmethyl) iminodiacetic acid; and N- (3-cyano-4-methyl-2-pyrrilcarbamoylmethyl) iminodiacetic acid. In one embodiment, the metal is chromium. In another embodiment of the invention, the targeting agent derived from metal is poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic acid)].

In yet another embodiment, the targeting agent is a targeting agent derived from biotin selected from the group consisting of biotin N-hydroxysuccinimide (NHS); sulfo-NHS-biotin; biotin N long chain hydroxysuccinimide; biotin sulfo-N-hydroxysuccinimide long chain; D-biotin; biocitin; sulfo-N-hydroxysuccinimide-S-S-biotin; Biotin-B CC; biotin-HPDP; iodoacetyl-LC-biotin; biotin hydrazide; biotin-LC-hydazidea biocytin hydrazide; biotin cadaverine; carboxybiotin; photobiotin; p-aminobenzoyl biocytin trifluoroacetate; p-diazobenzoyl biocytin; Biotin DHPE; Biotin-X-DHPE; 12 - ((biotinyl) amino) dodecanoic acid; succinimidyl ester of 12 - ((biotinyl) amino) dodecanoic acid; S-biotinyl homocysteine; biocytin-X; biocitin x-hydrazide; biotinyethylene diamine; biotin-XL; biotin-X-ethylenediamine; biotin-XX hydrazide; biotin-XX-SE; biotin-XX, SSE; biotin-X-cadaverine; a- (t-BOC) biocytin; N- (biotinyl) -N '- (iodoacetyl) ethylenediamine; DNP-X-biocitin-X-SE; biotin-X-hydrazide; norbiotinamine hydrochloride; 3- (N-maleimidylpropionyl) biocytin; ARP; biotin-l-sulfoxide; biotin methyl ester; biotin-maleimide; biotin-poly (ethylene glycol) amine; salt of | sodium (+) biotin 4-amidobenzoic acid; Biotin 2-N-acetylamino-2-deoxy-P-! D-glucopyranoside; Biotin-a-D-N-acetylneuraminide; Biotin-a-L-fucoside; Biotin! lacto-N-bioside; Biotin-Lewis-A trisaccharide; Biotin-Lewis-Y tetrasaccharide; Biotin-a-D-mannopyranoside; biotin 6-O-phospho-a-D-mannopyranoside; and 1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (biotinyl), iminobiotin derivatives; of the aforementioned compounds, and mixtures thereof. In another sub-modality of the invention, the agent of; The targeting is poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl] iminodiacetic acid]] and the therapeutic agent is insulin. In yet another sub-mode, the targeting agent is biotin DHPE or biotin-X-DHPE and the therapeutic agent is insulin. The present invention also discloses a method to make 'an orally bioavailable composition comprising gelatin and additional constituents, wherein the constituents comprise a liposome dynamically sized fragment liposome, and a particle, wherein the liposome fragment liposome, and the particle are generated from a mixture of lipid components, the composition further comprises at least one therapeutic agent or diagnostic agent, and optionally at least one targeting agent, wherein the gelatin actively interacts reversibly with one or more of the constituents . The method comprises the steps of mixing the lipid components, and optionally the at least one targeting agent in; aqueous media to form a first mixture; add the agent; therapeutic or diagnostic to the first mixture to form a second; mixture; adding the second mixture to the gelatin to form a mixture associated with gelatin; and drying the mixture associated with gelatin. In a sub-modality of the method, the lipid components are selected from the group consisting of MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristox-sn-glycero-3-; phosphocholine, cholesterol, cholesterol oleate, di-hexadecyl phosphate, 1,2-distearoyl-sn-: g I ice ro-3-f osfat, 1, 2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3 -fosfoetanolamina, 1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (succinyl), 1, 2-dipalmitoyl-sn-glycero-3- [phospho-rac- (1-glycerol)] (sodium salt ), and triethylammonium 2,3-diacetoxypropyl 2- (5 - ((3aS, 6aR) -2-oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl phosphate; and when present, the optional targeting agent is a targeting agent derived from metal or a targeting agent derived from biotin; and the therapeutic agent is selected from the group consisting of insulin, interferon, erythropoietin, parathyroid hormone, calcitonin, serotonin, rituximab, trastuzumab, uricase, tissue plasminogen activator, timoglobina, a vaccine, heparin or a heparin analogue, anitrombina III, filgrastin, ethyl pramilitida, exanatide, epifibatida, antiveninas, IgG, IgM, HGH, thyroxine, GLP-1, Factors VII and VIII clotting blood, a monoclonal antibody, and glycolipids that act as therapeutic agents. In another sub-modality of the method for making the orally bioavailable composition of the invention, the targeting agent derived from metal is poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic acid)]. In another sub-modality of the method for making the orally bioavailable composition of the invention, the targeting agent derived from biotin is selected from the group consisting of biotin DHPE and biotin-X-DHPE. According to another sub-modality of the invention, the agent Therapeutic is insulin. The present invention also contemplates a method for treating a disease in a human, the method comprising administering to the human; an orally bioavailable composition comprising gelatin and additional constituents, wherein the constituents comprise a liposome dynamically sized fragment liposome and lipid particle, wherein the lipid particle comprises at least one lipid component and the liposome or fragment liposome comprises at least two lipid components, and wherein the composition further comprises at least one therapeutic agent and, optionally, at least one targeting agent, wherein the gelatin actively interacts reversibly with one or more of the constituents. In a sub-modality of the method for treating disease, the disease is diabetes. In a further sub-modality, the lipid components are; select from the group consisting of MPB-PE, 1,2-distearoyl-sn-glycero-3-; phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-l glycero-3 Phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-, 3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1-2. dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (succinyl),, 2-dípalmitoil-sn-glycero-3- [phospho-rac- (1-glycerol)] (sodium salt), and triethylammonium 2,3- diacetoxypropyl 2- (5 - ((3aS, 6aR) -2-oxohexahydro-H-thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl phosphate; the so minus one or more therapeutic agents is insulin; and when it is present, the.

Optional addressing agent is an addressing agent: metal derivative or a targeting agent derived from biotin.

Even in another sub-modality, where the agent of addressing is not optional, the addressing agent is acidic poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic)], biotin DHPE, or biotin-X-DHPE.

In a preferred embodiment of the composition, the components Lipids are 1, 2 distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate, and cholesterol; the targeting agent is not optional and is polyfCr bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic acid)]; and the agent Therapeutic is insulin.

In another preferred embodiment, the lipid components are 1,2-distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate, and cholesterol; the agent Addressing is not optional and is Biotin-X-DHPE or Biotin DHPE; and the I, therapeutic agent is insulin.

In a preferred embodiment of a method of the invention, the: lipid components are 1, 2 distearoyl-sn-glycero-3-phosphocholine, dihexadecyl, phosphate, and cholesterol; the addressing agent is not optional and is acidic poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic)]; and the agent, Therapeutic is insulin.

In another preferred embodiment of the invention, the components Lipids are 1, 2 distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate, and cholesterol; the targeting agent is not optional and is Biotin-X-DHPE or Biotin DHPE; and the therapeutic agent is insulin. In another aspect of the invention, a composition of the invention can be made through a method comprising the steps of a) mixing at least three lipid components and, optionally, at least one targeting agent in aqueous media to form a first mixture wherein the lipid components are selected from the group consisting of MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1 , 2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1 , 2-dyristystl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (succinyl), 1 , 2-dipalmitoyl-sn-glycero-3- [phospho-rac- (1 -glycerol)] (sodium salt), and triethylammonium 2,3-diacetoxypropyl 2- (5 - ((3aS, 6aR) -2-i oxohexahydro-1 H-thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl phosphate; b) submit; the mixture to homogenization to form a mixture of liposomes; fragments of liposome, and particles; c) adding a therapeutic or diagnostic agent to the mixture of liposomes, liposome fragments, and particles-to create a second mixture; c) adding the second mixture to the gelatin-to form a mixture associated with gelatin, and; d) drying said mixture with gelatin. The invention further includes a method of treating diabetes in; a human. This method comprises administering to said human a orally bioavailable composition comprising gelatin and additional constituents, said constituents comprise a dynamically sized liposome, liposome fragment, and lipid particle, wherein said lipid particle comprises at least one lipid component and said liposome or liposome fragment comprises at least minus two lipid components, said composition further comprises insulin and, optionally, at least one targeting agent, wherein said gelatin actively interacts reversibly with one or more of said constituents. The method further comprises co-administering insulin to said human. The present invention also includes a kit comprising an orally bioavailable composition comprising gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment, and lipid particle, wherein said lipid particle comprises at least one lipid component and said liposome or liposome fragment comprises at least two lipid components, said composition further comprising at least one therapeutic or diagnostic agent and, optionally, at least one targeting agent, wherein said gelatin actively interacts reversibly with one or more of said constituents. The kit additionally includes instructional material for the administration of said composition to a human. In a sub-mode of the kit of the invention, the kit includes in addition insulin for co-administration with said composition to said human.

BRIEF DESCRIPTION OF THE DRAWINGS : The above explanation, as well as the following description Detailed description of preferred embodiments of the invention will be better understood when read together with the attached drawings. For the purpose of polishing the; invention, the modalities which are currently preferred are shown in the drawings. However, it must be understood that the invention does not is limited to the precise dispositions and mediations shown.

Figure 1 is a schematic representation of a composition of the invention.

Figure 2 is a graph that represents the counts of ' radiolabelled phospholipid 14C found in the femoral veins and ports 15 and 'i 30 minutes after injecting radio-labeled composition into the duodenum of! I one of 230 grams fasting and anesthetized. ! Figure 3 is a bar graph representing the distribution; of radiolabelled phospholipid 14C between blood, liver, and spleen in rats 1 of Figure 2, after sacrifice.

Figure 4 is a graph representing the absorption of radio-labeled composition of drinking water at 15, 30, and 45 minutes after 1 of dosage.

Figure 5 is a bar graph representing the distribution of the marked composition between the blood, liver, and spleen in the rats of the Figure 4, after sacrifice.

Figure 6 is a graph representing the efficacy of insulin ' orally administered in the form of a composition of the invention.

Figure 7 is a bar graph depicting the efficiency of a composition of the invention (in low dosages), to convert a ' diabetic dog type 2 of hepatic glucose production to uptake during a portal glucose load.

Figure 8 is a scheme of blood calcium levels after the administration of calcitonin associated with a composition not address of the invention.

Figure 9 is a graph representing the distribution of size of the constituent members of a composition of the invention.

Figure 10 is a graph of the efficacy of a composition of the invention comprising a biotin and insulin targeting agent in reducing the effects of type 2 diabetes in humans.; Figure 11 is a chromatogram of a composition of the invention showing the efficacy of insulin loading.

Figure 12 is a graph showing the efficiency of oral supply of IgG antibodies covalently bound to a composition of the invention against oral absorption of non-IgG antibodies associated (free).

Figure 13 is a graph depicting the effect of oral administration of thyroxine associated with a composition of the invention on serum cholesterol and triglycerides ("TG") in mice. Figure 14 is a graph depicting the effect of oral administration of interferon associated with a composition of the invention to reduce viral load in humans suffering from hepatitis C.

DETAILED DESCRIPTION OF THE INVENTION The present invention includes compositions that facilitate and / or allow the absorption of therapeutics which are not usually orally bioavailable. In one embodiment, a composition of the invention functions by association with a therapeutic agent and accompanying the therapeutic agent through the lumen of the intestine to the portal blood flow and finally into the systemic circulation. In certain embodiments, the composition of the invention possesses many unique and advantageous properties. One of these properties is the ability to insert into intercellular spaces and cross the mammalian intestine into the portal circulation. In certain embodiments, a composition of the invention can be targeted to specific cellular or extra-cellular receptors through one or more targeting agents. In a typical embodiment, an orally bioavailable composition of the invention comprises gelatin and additional constituents.

Additional constituents comprise a dynamically sized liposome, liposome fragment, and lipid particle, wherein the lipid particle comprises at least one lipid component and the liposome or liposome fragment comprises at least two lipid components. The composition further comprises at least one therapeutic or diagnostic agent, and optionally at least one targeting agent. Gelatin actively interacts reversibly with one or more of the constituents in the composition of the invention.

Definitions Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one skilled in the art to which the invention pertains. Generally, the nomenclature used herein and in the laboratory procedures in organic chemistry and protein chemistry are those known and commonly employed in the art. The articles "a" and "an" are used herein to refer to one or more than one (ie, to at least one) of the grammatical object of the article. By way of example, "an element" means an element or more than one element. As used herein, amino acids are represented by their full name, by the three letter code as well as the code of a letter corresponding thereto, as indicated in next box: Name Code Code Name Full Code Code 3 Letters 1 Complete Letter 3 Letters 1 Letter Alanina Wing A Leucine Leu L Arginine Arg R Lysine Lys K Asparagine Asn N Methionine Met M Aspartic Acid Asp D Phenylalanine Phe F Cysteine Cys C Proline Pro P Cystine Cys Cys CC Serine Ser S Glutamic Acid Glu E Threonine Thr T Glutamine Gln Q Tryptophan Trp w Glycine Gly G Tyrosine Tyr And Histidine His H Valine Val V Isoleucine Me I The term "lower", when used with reference to a chemical structure, describes a group containing from 1 to 6 atoms of carbon.

The term "alkyl", by itself or as part of another; Substituent means, unless otherwise stated, a straight, branched or cyclic hydrocarbon with the number of carbon atoms: designated (ie, C1-C6 means one to six carbons). Examples; include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tere-butyl, pentyl; neopentyl, hexyl, cyclohexyl and cyclopropylmethyl. The alkyl is preferred more C1-C3, particularly ethyl, methyl and isopropyl.

The term "alkylene", by itself or as part of another: substituent means, unless stated otherwise, a: straight chain, branched or cyclic hydrocarbon with two sites of: substitution, for example, methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-C (CH3) = CH-), etc. The term "aryl", used alone or in combination with other terms, means unless otherwise stated, a carbocyclic structure, with or without saturation, that contains one or more rings (typically one, two or three rings) wherein said rings may be joined in a pendant form, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. The structure can be optionally substituted with one or more substituents, independently selected from halogen; CrC6 alkyl; CrC6 alkenyl; Ci-C6 alkoxy; OH; NO2; C = N; (C2-C6) alkylene-OR2; phosphonate; NR22; NHC (= O) (CrC6) alkyl; sulfamyl; carbamyl; OC (= O) (C C3) alkyl; O (C2-C6) alkylene-N ((Ci-C6) alk) 2; Y (Ci-C3) perfluoroalkyl. The term "arylalkyl lower" means a functional group in which an aryl group is attached to a lower alkylene group, for example, -CH2CH2-phenyl. The term "alkoxy" used alone or in combination with other terms means, unless stated otherwise, an alkyl group or an alkyl group containing a substitute such as a hydroxyl group, with the designated number of carbon atoms connected to the rest of the molecule by means of an oxygen atom, such as, for example, -OCH (OH) -, -OCH2OH, methoxy (-OCH3), ethoxy (-OCH2CH3), -propoxy (- OCH2CH2CH3), 2-propoxy (isopropoxy), butoxy (-OCH2CH2CH2CH3), pentoxy (-OCH2CH2CH2CH2CH3), and homologues and higher isomers. The term "acyl" means a functional group of the general formula -C (= 0) -R, wherein -R is hydrogen, alkyl, amino or alkoxy. Examples include acetyl (-C (= 0) CH3), propionyl (-C (= 0) CH2CH3), benzoyl (-C (= 0) C6H5), phenylacetyl (C (= 0) CH2C6H5), carboethoxy (-CO2CH2CH3) , and dimethylcarbamoyl (C (= 0) N (CH3) 2). The terms "halo" or "halogen" by themselves or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine or iodine atom. The term "heterocycle" or "heterocyclyl" or "heterocyclic" by itself or as part of another substituent means, unless otherwise stated, a saturated or unsaturated, stable, mono or multicyclic ring system comprising carbon and at least one heteroatom selected from the group comprising N, O, and S, and wherein the sulfur and nitrogen heteroatoms may optionally be oxidized and the nitrogen atom optionally quaternized. Examples include pyridine, pyrrole, imidazole, benzimidazole, phthalein, pyridinyl, pyranyl, furanyl, thiazole, thiophene, oxazole, pyrazole, 3-pyrroline, pyrrolidene, pyrimidine, purine, quinoline, isoquinoline, carbazole, etc. Where the substitution will result in stable compounds, the structure can be optionally substituted with one or more substituents, independently selected from halogen; C-i-C6 alkyl; C-i-C6 alkenyl; C1-C6 alkoxy; OH; NO2; C = N; C (= 0) 0 (C C3) alkyl; (C2-C6) alkylene-OR2; phosphonate; NR22; NHC (= 0) (C1-C6) alkyl; sulfamyl; carbamyl; OC (= 0) (C -C3) alkyl; 0 (C2-C6) alkylene-N ((Ci-C6) alk) 2; and (C C3) perfluoroalkyl. The term "unfriendly lipid" means a lipid molecule with a polar end and a non-polar end. A "complexing agent" is a compound capable of forming a coordination complex insoluble in water with a metal, for example, a salt of chromium, zirconium, etc., which is substantially insoluble in water and soluble in organic solvents. "Aqueous media" means means comprising water or media comprising water containing at least one pH or salt buffer. The terms "related" or "related to" when used with reference to a composition or constituent of a composition of the invention, mean that the aforementioned material is incorporated (or interspersed) in, or on the surface of, or within a composition or a constituent of a composition of the present invention. The term "insulin" refers to natural or recombinant forms of insulin, synthetic insulin, and derivatives of the aforementioned insulins. Examples of insulin include, but are not limited to, insulin lispro, aspartate insulin, regular insulin, glargine insulin, zinc insulin, extended human zinc insulin, isophane insulin, regulated human regular insulin, insulin glulisine, recombinant human regular insulin, ultralente insulin, humulin, NPH insulin, Levemir, Novolog, and recombinant human isophane insulin. Also included are animal insulins, such as bovine or porcine insulin. The terms "glargine" and "insulin glargine" both refer to a recombinant human insulin analogue that differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C terminus of chain B. Chemically, it is 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin and has the empirical formula C267H404 72O78S6 and a molecular weight of 6063. The term "recombinant human isophane insulin" refers to a human insulin that has been treated with protamine. The term "bioavailability" refers to a measurement of the rate and degree at which a pharmaceutical agent, such as, but not limited to, insulin, reaches the systemic circulation and is available at its site of action. As used in this, "treat" means to reduce the frequency with which the symptoms of a disease, disorder or adverse condition and the like, are experienced by a patient. As used herein, the term "pharmaceutically acceptable carrier" means a chemical composition with which the active ingredient can be combined and which, after combination, can be used to deliver the active ingredient to a subject. The term "lipid" or "lipids" means an organic compound [ characterized by its preference to non-polar aprotic organic solvents. A lipid may or may not possess an alkyl tail. Lipids according to the present invention include, but are not limited to, the class of compounds known in the art such as phospholipids, cholesterols, and dialkyl phosphates. As used herein, "cholesterol" means the compound and all derivatives and analogs of the compound: As used herein, "particle" comprises an agglomeration of multiple units of one or more lipids. As used herein, "thyroxine" refers to the compound: wherein the amino group can be in any of the "D" or "L" configuration. As used herein, "co-administration" or "co-administration" as well as variations thereof, means administering a second therapeutic agent before, during or after administration to a first therapeutic agent. The first and second therapeutic agents! They can be different or different. As used herein, "interferon" refers to all forms of interferon, including, but not limited to, interferon-a, interferon-beta, interferon-gamma, as well as subunits thereof.

DETAILED DESCRIPTION OF THE INVENTION A composition of the present invention is comprised of gelatin and one or more constituents wherein said constituents include liposomes, liposome fragments and lipid particles. Traditionally, liposome, liposome fragments, and lipid particles comprised of amphipathic materials have been limited to a smaller size distribution of about 40 nanometers. It is believed that this limit is a function of the collective sizes of the constituent lipids (phospholipids, cholesterols, dialkyl phosphates, etc.) that constituted the structure of the membrane. The constituents of a composition of the present invention, however, have heretofore shown unobserved dynamic sizing and size elasticity. Specifically, the constituents of the compositions of the present invention exist in a dynamic equilibrium in aqueous media wherein the constituents, on average, range in size from about 6 nanometers to about 60 nanometers in diameter. At any given moment, somewhere from around 5% to about 50% of the constituents have an average diameter of about 20 nanometers or less. Due to the almost constant fluctuations in sizes, the constituents of the compositions of the present invention can not be physically separated by conventional fractionation means to form discrete populations of structures measured differently. The constituents of a composition of the invention can be, but are not limited to, a liposome, a liposome fragment, and a lipid particle. The constituents of the composition of the present invention can be related to one or more therapeutic agents and / or diagnostic agents. Without wishing to be bound by any particular theory, it is believed that constituents having diameters of 20 nanometers or less are small enough to pass through the intercellular spaces thus allowing the transport of the related therapeutic agents or diagnostic agent of the lumen of the bowel. in the portal blood. The associated therapeutic agents and / or diagnostic agents can be covalently or non-covalently linked to one or more constituents of the composition of the present invention. In embodiments of the invention wherein the therapeutic or associated diagnostic agents are covalently linked, the associated therapeutic agent or diagnostic agent can be attached to a chemical group that can be functional. Examples of functional groups include, but are not limited to, hydroxy, amino, carboxy, and amido groups.

Examples of therapeutic agents that can be covalently linked to a constituent of a composition of the present invention include polypeptides and / or proteins, such as, but not limited to,; GLP-1, insulin, calcitonin, interferon, uricase, tissue plasminogen activator, thymoglobin, various vaccines, heparin, heparin analogs, antithrombin III, filgrastin, pramilitide acetate, exenatide, epifibatide, and antivenins, including blood coagulation factors , but not limited to, Factors VII and VIII, several small molecules, such as, for example, D or L thyroxine or serotonin, nucleic acids, DNA or RNA sequences, immunoglobulins, such as, but not limited to, IgG and IgM, and a variety of monoclonal antibodies, such as, but not limited to, rituximab, trastuzumab, and glycolipids that act as therapeutic agents, and in addition, other larger proteins, such as, for example, human growth hormone ("HGH"), erythropoietin, and parathyroid hormone. Examples of diagnostic agents that can join! covalently to a constituent of a composition of the present invention include diagnostic contrast agents such as, but not limited to, gold and gadolinium. Other diagnostic agents include radioactive materials such as radioactive isotopes of common atoms which; include, but are not limited to, 13C, 68Ge, 18F, and 125l. These contrast agents and radioactive agents can be covalently linked to a constituent of the composition directly through covalent attachment to a component. Lipids or targeting agent. Alternatively, and wherever, chemically appropriate, the diagnostic agent can be linked to a ligand such as DADO (2'-deoxyadenosine), which by itself is covalently attached to a lipid component or targeting agent. Alternatively, and where chemically appropriate, a constituent of a composition of the invention can be associated with the aforementioned diagnostic or therapeutic agents by means of non-covalent interactions. The non-covalent interactions allow the compatibility of a constituent of the composition of the present invention with a wide variety of diagnostic and therapeutic agents.

Lipids A constituent of a composition of the present invention comprises one or more lipid components and an optional targeting agent. An embodiment comprising a single unit or multiple units of a single lipid component is referred to herein as: a "lipid particle". A modality comprising two or more different ones; lipid components and an optional targeting agent is classified as a liposome or liposome fragment, depending on the nature of the resulting structure. The lipid components of the present invention are selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn- glycero-3-phosphocholine, cholesterol, cholesterol oleate, dihexadecyl phosphate,, 2-distearoyl-sn-glycero-3-, phosphate, 1, 2-dipalmito'il-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1, 2- dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (succinyl), 1,2-dipalmitoyl-sn-glycero-3- [phospho-rac- (1 -glycerol)] (sodium salt), triethylammonium 2,3- diacetoxypropyl 2- (5 - ((3aS, 6aR) -2-oxohexahydro-1 H -thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl phosphate, MPB-PE and derivatives thereof. The representative structures are presented in table 1.

TABLE 1 By way of non-limiting examples, the constituents of a composition of the present invention can be formed of lipid components mixed according to the following: Approximately 61 mole percent of 1,2-distearoyl-sn-glycero-3-phosphocholine, approximately 22 percent one hundred mole of dihexadecyl phosphate, and approximately 16 mole percent of cholesterol. In embodiments wherein a constituent incorporates a targeting agent, the aforementioned mixture may further include from about 1 to about 2 mole percent of at least one targeting agent, with the amounts of others: reduced lipid components to maintain the relation of the components established above. In another embodiment, a composition of the present invention can be formed of lipid components mixed in accordance with the following: about 68 mole percent of 1,2-dipalmitoyl-sn-glycerol-1 3-phosphocholine, approximately 18 mole percent dihexadecyl phosphate; about 9 mole percent cholesterol, and about 3 percent mole percent of MPB-PE. In modalities where a constituent incorporates a targeting agent, the mix named above! It can also include from about 1 to about 2 percent molar of at least one targeting agent, with the amounts of other lipid components reduced to maintain the ratio of the previously established components.

Preparation Generally, the constituents of a composition of the present invention are formed when at least one lipid component and optional targeting agent are homogenized in an aqueous medium by means of microfluidization or another procedure involving cavitation.

In one embodiment of the invention, the component (s); I lipid (s) and optional addressing agent (s) may be; homogenized in 18 mM phosphate buffer at a pH of > about 6.0 at a pH of about 8.0. The concentration of lipid component in the phosphate regulator can range from about 10 to about 200 mg / ml and any and all of the total and partial integers between them. In one modality, the concentration of, lipid component is from about 30 to about 150 mg / ml. In a more preferred embodiment, the concentration of the component lipid is from about 15 to about 50 mg / ml. In the most preferred embodiment, the concentration of the lipid component is about 28-30 mg / ml. The homogenization of the aqueous media, the lipid component (s), and optional targeting agent can be achieved by treatment in a device suitable for homogenization. Examples of suitable devices include, but are not limited to, a Polytron® PT 6100 System, an M-1 10-EH microfluidizer, an ultrasonic sonicator, a high pressure membrane filtration apparatus, and a homogenizing extruder. In cases where a microfluidizer is used, the microfluidizer is preferably operated at a temperature that is higher than the higher transition temperature of a lipid component and more preferably at a temperature greater than about 75 ° C. Thus, the elevated temperature allows any acyl and alkyl chains present in the lipid components to move fluidly and also conform to and relate to the attached hydrocarbon moieties. These non-covalent associations directly result in the formation of a constituent of a composition of the present invention. For the microfluidization procedure, up to about five independent steps are required at 632.7 Kg / cm2 gauge to achieve dynamic constituent measurement with some constituents having radii of less than 20 nanometers. The constituent analysis data generated by a Coulter N-4 Plus Sutn Mieras Particle Size Analyzer is shown in Figure 9 and represents 10 repeated size analyzes in the same sample as it remained stationary in the Particle Size Analyzer. Sub-Micras Coulter N-4 Plus. These data demonstrate the dynamic nature of the constituent size and the; fluid nature of the interactions between the constituents of the composition of the present invention in aqueous media. ' After microfluidization, the resulting constituents can be filtered by sterilization through a Supor ™ series membrane of 0.8 microns to 0.2 microns. During the process of forming submicron particles, hydrogen bonding, ionic bonding, van der Waal interactions, dipolar interactions, ion-dipole interactions and hydrophobic associations1 dictate the manner in which the constituents of a: composition of the present invention. Although it is not desired to be limited to any particular theory, it is believed that the interaction of all these forces, at various degrees, under the conditions mentioned above, leads to the 1 dynamically measured constituents of the present invention.

Incorporation of a targeting agent In certain embodiments, a constituent of the present invention may optionally comprise a targeting agent.

The targeting agents alter a Dio-distribution of the constituent, and further improve the efficacy of an associated therapeutic agent. For example, a constituent of a composition of the present invention can incorporate one or more targeting agents that act to direct the. constituent to a specific cellular or extracellular receptor. Alternatively, by way of a non-limiting example, the targeting agent can mask the constituent of the reticuloendothelial (macrophage) recognition. In one embodiment, a targeting agent facilitates delivery of insulin to the liver to control post-prandial glycogen storage and encompasses a class of molecules referred to as a "hepatocyte targeting molecule" (HTM). Examples of HTM include targeting agents derived from biotin such as 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamin-N- (biotinyl) and targeting agents derived from metal such as poly [Cr-bis (N- 2,6-; diisopropylphenylcarbamoylmethyrinodiacetic acid)]. The agents of! targeting metal derivatives and targeting agents: biotin derivatives are discussed below and are fully described in: US Patents. 7,169,410 and 4,603,044 and PCT application PCT / US06 / 191 19; : and Patent Applications of E.U.A. 1 1 / 384,728 and 1 1 / 384,659. Examples: additional targeting agents derived from biotin are described in table 2. When the targeting agent comprises biotin, iminobiotin, carboxybiotin, biocytin, or iminobiocitin, the biotin, iminobiotin, carboxybiotin, biocytin, or iminobiocitin molecules can be joined via an amide bond to the nitrogen of a phospholipid molecule such as 1,2-dipalmitoyl-sn-glycero- 3-phosphoethanolamine. The compounds can also be linked to a molecule such as cholesterol through an ester linkage. In the case of biocytin and iminobiocitin, the compounds can be linked to benzoyl thioacetyl triglycine by means of an amide bond between the terminal nitrogen of iminobiocytine and the carbonyl terminal of benzoyl thioacetyl triglycine. Alternative bonding connectivities to those described above are possible and are considered within the scope of the present invention TABLE 2 Compound names 48-50: 48. ((2R, 5S) -3-acetamido-5-hydroxy-6- (hydroxymethyl) -2, 3,4,6-tetramethyl-4 - (( ((2S, 5R) -3,4,5-trihydroxy-6- (hydroxylmethyl) -2,3,4,5,6-pentamethyltetrahydro-2H-pyran-2-yl) methoxy ) methyl) tetrahydro-2H-pyran-2-yl) methyl 5 - ((3aS, 6aR) -2-oxohexahydro-1 H -thieno [3,4-d] imidazol-4-yl) pentanoate ((2R, 5S) -3-acetamido-5-hydroxy-6- (hydroxymethyl) -2,3,4,6-tetramethyl-4 - ((((2S, 5R) - 3,4,5-trihydroxy-6- (hydroxymethyl) -2,3,4,5,6-pentamethyltetrahydro-2H-pyrn-2-yl) methoxy) methyl) tetrahydro-2H-pyran-2-yl) methyl 5 - ((3aS, 6aR) -2-oxohexahydro-1-Hetien [3,4-d] imidazol-4-yl) pentanoate 49. (2R , 3R, 5S) -5 - ((((2S, 3S, 5S) -3-acetamido-5-hydroxy-6- (hydroxylmet) -2,4,6-tr methyl-4 - ((((2S, 5R) -3,4,5-trihydroxy-6- (hydroxymethyl) -2,3,4,5,6-pentamethyltetrahydro-2H-p Ran-2-yl) methoxy!) Methyl) tetrahydro-2 H -pyran-2-yl) methoxy) methyl) -3,4-d, h, d, x-2,4,5,6, 6-pentamethyl-tetrahydro-2H-pyrn-2-yl 5 - ((3aS, 6aR) -2-oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) pentanoate 50. ( 2S, 5 S) -3-acetamido-4 - ((((2R, 5S) -5 - ((((2R, 5S) -4,5-dihydroxy-6- (hydroxymethyl) -2, 3,4, 5,6 -pentamethyl-3 - ((((2S, 5S) -3,4,5-tnhidrox¡-2, 3,4, 5,6,6-hexametiltetrahidro-2H-piran-2-yl) methoxy) methyl) tetrahydro -2H-pyrn-2-yl) methoxy) methy1) -3,4-dihydroxy-2,3,4,5,6,6-hexamethyltetrahydro-2H-pyran 2-yl) methoxy) methyl) -5-hydroxy-6- (hydroxymethyl) -2,3,4,5,6-pentamethyltetrahydro-2H-pyran-2-yl 5 - ((3aS, 6aR) -2 -oxohexahydro-1 H-tieno [3,4-d] ¡madazol-4-yl) pentanoate The structures of the iminobiotin compounds are not shown in Table 2. However, the iminobiotin structures are analogous of the biotin structure where the biotin group is replaced by an iminobiotin group. An example is shown below.

N-hydroxysuccinimide biotin N-hydroxysuccinimide iminobiotin In one embodiment of the invention, the targeting agents derived from metals can be polymeric or monomeric. The targeting agents derived from polymeric metal are completely described in U.S. 7,169,410. The targeting agents derived from monomeric metal are completely described in U.S. 4,603,044. Whether polymeric or monomeric, the compounds are generally a metal (typically purchased as an inorganic salt) that can be selected from transition metals and interior transition metals or neighboring transition metals. The transition metals and interior transition from which the metal is selected include: Se (scandium), Y (yttrium), La (lanthanum), Ac (actinium), the actinide series; Ti (titanium), Zr (zirconium), Hf (hafnium), V (vanadium), Nb (niobium), Ta (tantalum), Cr (chromium), Mo (molybdenum), W (tungsten), Mn (manganese), Te (technetium), Re (rhenium), Fe (iron), Co (cobalt), Ni (nickel), Ru (ruthenium), Rh (rhodium), Pd (palladium), Os (osmium), Ir (iridium and Pt) (Platinum) The neighbors of the transition metals from the which metal can be selected include: Cu (copper), Ag (silver), Au (gold), Zn (zinc), Cd (cadmium), Hg (mercury), Al (aluminum), Ga (gallium), In (Indian), TI (thallium), Ge (germanium), Sn (tin), Pb (lead), Sb (antimony) and Bi (bismuth) and Po (polonium). Preferably the metal is chromium.

Non-limiting examples of useful salts include chromium chloride (III) hexahydrate; chromium (III) fluoride tetrahydrate; chromium bromide (III) hexahydrate; zirconium citrate (IV) and ammonium complex; chloride zirconium (IV); zirconium fluoride (IV) hydrated; zirconium iodide (IV); molybdenum bromide (III); molybdenum chloride (III); molybdenum sulfide (IV); iron hydrate (III); iron (III) phosphate tetrahydrate, sulfate iron (III) pentahydrate and the like.

In addition to a metal, the targeting agent derived from metal comprises one or more complexing agents. An agent complex former is a compound capable of forming a complex of insoluble coordination in water with the preferred metal. There are several families of suitable complexing agents.

A complexing agent can be selected from the family of iminodiacetic acids of formula (1) wherein R \ is alkyl lower, aryl, lower arylalkyl, or a heterocyclic substituent.

HO C II- CH2- - CH2- C II OH I (I) Lower alkylene I C N R O H Suitable compounds of formula (1) include: N- - ((2,6-diisopropilfenilcarbamoilmetil) iminodiacetic; N- - ((2,6-dietilfenilcarbamoilmetil) iminodiacetic; N- - ((2,6-dimetilfenilcarbamoilmetil) iminodiacetic N- - ((4-butilfenilcarbamoilmetil) iminodiacetic;; N- - ((2,3-dimetilfenilcarbamoilmetil) iminodiacetic; -; ((4-isopropilfenilcarbamoilmetil) iminodiacetic acid N N- - ((2,4-dimetilfenilcarbamoilmetil ) iminodiacetic; N- - ((2,5-dimetilfenilcarbamoilmetil) iminodiacetic; áácciiddoo N N - ((3,4-dimetilfenilcarbamoilmetil) iminodiacetic acid; N- (3,5-dimetilfenilcarbamoilmetil) iminodiacetic; N- - (( 3-butilfenilcarbamoilmetil) iminodiacetic; N- - ((2-butilfenilcarbamoilmetil) iminodiacetic; N- - ((4-tertiary butilfenilcarbamoilmetil) iminodiacetic; áácciiddoo N N - ((3-butoxifenilcarbamoilmetil) iminodiacetic; N- - (( 2-Hexyloxyphenylcarbamoylmethyl) iminodiacetic; N- - ((4-hexyloxyphenylcarbamoylmethyl) iminodiacetic acid; am nodiacetic acid; N- (3-bromo-2,4,6-trimethylphenylcarbamoylmethyl) iminodiacetic acid; benzimidazolmethyl iminodiacetic acid; N- (3-cyano-4,5-dimethyl-2-pyrrilcarbamoylmethyl) iminodiacetic acid; N- (3-cyano-4-methyl-5-benzyl-2-pyrrilcarbamoylmethyl) iminodiacetic acid; and N- (3-cyano-4-methyl-2-pyrrilcarbamoylmethyl) iminodiacetic acid and other N- (3-cyano-4-methyl-2-pyrrilcarbamoylmethyl) iminodiacetic acid derivatives of formula (2), where R2 and R3 are the following: R2 Ra H ISSO-C4H9 H CH2C6H4-p-OH CH3 CH3 CH3 ISSO-C4H9 CH3 CH2CH2SCH3 CH3 C6H5 CH3 CH2C6H4-p-OCH3 Alternatively, the complexing agent can be selected from the family of iminodiaid derivatives of formula (3), wherein R4, R5, and R6 are independently selected each time present and can be hydrogen, lower alkyl, aryl, lower annihil, lower alkoxyalkyl and heterocyclic. Q O R "0 C Lower alkylene! ^ Lower alkylene C O R6 (3) *5 Suitable compounds of formula (3) include: N '- (2-acetylnaphthyl) iminodiacetic acid (NAIDA); N '- (2-naphthylmethyl) iminodiacetic acid (NMIDA); iminodicarboxymethyl-2-naphthyl ketone phthalein complexone; 3 (3: 7a: 12a: trihydroxy-24-norcol anil-23-iminodiacetic; acid benzimidazolmethyliminodiacetic; and N- (5, pregneno-3-p-ol-2-oil) acid carbamoylmethyl) iminodiacetic.

The complexing agent can also be selected of the amino acid family of formula (4), O H- C O R8 (4) wherein R7 is an amino acid side chain; where R8 it can be lower alkyl, aryl and arylalkyl lower; and where Rg is pyridoxylidene.

Suitable amino acids of formula (4) are amino acids aliphatic, including without restriction: glycine, alanine, valine, leucine, isoleucine; hydroxy amino acids, including serine, and threonine; amino acids dicarboxylics and their amides, including aspartic acid, asparagine, acid glutamic, glutamine; amino acids that have basic functions, including lysine, hydroxylysine, histidine, arginine; aromatic amino acids, including phenylalanine, tyrosine, tryptophan, thyroxine; and amino acids that contain sulfur, including and methionine.

The complexing agent can also be selected of amino acid derivatives including, without restriction (3-alanine-y-amino) butyric acid, O-diazoacetylserine (azaserine), homoserine, ornithine, citrulline, penicillamine and members of the class of pyridoxylidene compounds.

Pyridoxylidene compounds include, without restriction: pyridoxylidene glutamate; pyridoxylidene isoleucine; pyridoxylidene phenylalanine; pyridoxylidene tryptophan; pyridoxylidene-5-methyl tryptophan; pyridoxylidene-5-hydroxytryptamine; and pyridoxylidene-5-butyltriptamine.

The complexing agent can also be selected of the diamine family of formula (6), RuCOORto J12 N Lower alkylene (6) R- | 1 COORig wherein Rio is hydrogen, lower alkyl or aryl; Rn is lower alkylene or lower arylalkyl; R 2 and R 13 are selected independently every time they show up and they can be hydrogen, lower alkyl, alkyl, aryl, arylalkyl, acylheterocyclic, toluene, sulfonyl or tosylate.

Examples of suitable diamines of the formula (6) include, but are not limited to, ethylenediamine-N, N-diacetic acid; ethylenediamine-N, N-bis (-2-hydroxy-5-bromophenyl) acetate; N'-acetylethylenediamine-N, N-diacetic acid; N'-benzoyl ethylenediamine-N, N-diacetic acid; N '- (p-toluenesulfonyl) ethylenediamine-N, N-diacetic acid; N '- (p-t-butylbenzoyl) ethylenediamine-N, N-diacetic acid; N '- (benzenesulfonyl) ethylenediamine-N, N-diacetic acid; N'- (p-chlorobenzenesulfonyl) ethylenediamine-N, N-diacetic acid; N '- (p-ethylbenzenesulfonyl ethylenediamine-N, N-diacetic acid; N'-acyl and N'-sulfonyl-ethylenediamine-N, N-diacetic acid; N'- (pn-propylbenzenesulfonyl) ethylenediamine-N, N-diacetic acid; N- (naphthalene-2-sulfonyl) ethylenediamine-N, N-diacetic acid, and N'- (2,5-dimethylbenzenesulfonyl) ethylenediamine-N, N-diacetic acid Other non-limiting examples of compounds or complexing agents include penicillamine; p-mercaptoisobutyric acid, dihydrothioctic acid, 6-mercaptopurine, cetoxal-bis (thiosemicarbazone), complexes of amine hepatobiliary, 1-hydrazinophthalazine (hydralazine), sulfonyl urea, complexes of Schiff base of hepatobiliary amino acids, pyridoxylidene glutamate, pyridoxylidene isoleucine, pyridoxylidene phenylalanine pyridoxylidene tryptophan, pyridoxylidene 5-methyl tryptophan, pyridoxylidene-5-hydroxytryptamine, pihdoxylidene-5-butyltriptamine, tetracycline, 7-carboxy-p-hydroxyquinoline, phenolphthalein, eosin I blue, eosin I yellowish, see ograffin; 3-hydroxyl-4-formyl-pyridine glutamic acid; substituted Azo iminodiacetic acid; hepatobiliary die complexes, such as rose bengal; Congo red bromosulfophthalein; bromophenol blue; blue toluidine; and Indocyanine green; hepatobiliary contrast agents, such as iodipamide; and yogic acid; bile salts, such as bilirubin; colgicilyodohistamine; and thyroxine; thio hepatobiliary complexes, such as penicillamine; p-mercaptoisobutyric acid; dihydrothiocytic acid; 6-mercaptopurine; and cetoxal-bis (thiosemicarbazone); hepatobiliary amine complexes, such as 1-hydrazinophthalazine (hydralazine); and sulfonyl urea; Schiff base complexes of hepatobiliary amino acids, including pyridoxylidene-5-hydroxytryptamine; and pyridoxylidene-5-butyltriptamine; hepatobiliary protein complexes, such as protamine; ferritin; and asialo-orosomucoid; and lozenge complexes, such as lactosamine albumin; immunoglobulins, G, IgG; and hemoglobin.

Addition of therapeutic agents As previously mentioned, in certain embodiments, one or more therapeutic agents may be associated with a constituent of a composition of the present invention. Examples of therapeutic agents include, but are not limited to, insulin, interferon, rituximab, trastuzumab,: uricase, tissue plasminogen activator, thymoglobin, various vaccines,, heparin, heparin analogs, anithrombin III, filgrastin, pramilitide acetate, exanatide, epifibatide , antivenias, IgG, IgM, Factors VII and VIII of blood coagulation, HGH, GLP-1, erythropoietin, parathyroid hormone, serotonin, Do L-thyroxin, calcitonin, monoclonal antibodies, as well as other therapeutic peptides. In certain modalities, a therapeutic agent, such as insulin, associates with a constituent of a composition of the present invention. In one embodiment, the association is achieved with the addition of a low molarity insulin solution to an aqueous suspension of constituents. In this embodiment, the number of lipid molecules involved in the assembly of the constituents far exceeds the number of interlaced and / or combined insulin molecules, either in or within the constituent matrices. The high ratio of constituents to insulin minimizes the molecular interactions between insulin and the constituents, ensuring that the self-assembly and self-organization process of the constituents of the composition of the present invention are not affected. This high ratio facilitates the formation of a stable constituent / insulin association. Without wishing to be bound by a particular theory, it is believed that the amount of therapeutic agent (s) associated with a constituent of a composition of the present invention appears to be a function of loading time and concentration of lipids. As the concentration of the lipid component in the aqueous medium increases, additional therapeutic agents are associated with a constituent of a composition of the present invention. The time required for loading the therapeutic agent can be from several hours to about a week. The low concentration of the therapeutic agent relative to the concentration of the constituents of the composition of the present invention is unique among the lipid particle delivery systems.

Normally liposomes or liposome-type delivery systems have been using a much greater amount of therapeutic agent. The!; efficacy of this embodiment of the present combination demonstrates that it is possible to use less therapeutic agent and still obtain a pharmacologically desirable result in the patient. Therefore this embodiment of the invention provides an advantageous therapeutic option. In other embodiments, the addition of a higher concentration1 of therapeutic agent may be both desirable and advantageous. The constituent members of a composition of the present invention are! able to associate with, and tolerate, solutions of any therapeutic agent since they have a higher molarity. A schematic example of a modality of a constituent of the composition of the present invention is shown in Figure 1. Figure 1 illustrates a constituent / HTM / insulin construct. Insulin molecules are bound to the surface of the constituent by means of: non-covalent electrostatic interactions. Serotonin can also be given to the liver, like: insulin, used a constituent / HTM complex according to the! invention. Serotonin acts together with insulin at the level of the liver to activate hepatic glucose storage during a portal (oral) glucose load. To achieve the desired effect, serotonin must be administered to the liver. Unaddressed serotonin, introduced by injection or oral delivery in pharmacologically acceptable doses, can not: effectively induce the desired activity. Therefore, one embodiment of the invention comprising a constituent / HTM / serotonin construct provides a highly desirable delivery mechanism for this important glycoregulatory hormone. In one embodiment of the invention that is designed for the serotonin delivery, the lipid components selected from the constituents of the composition include approximately 62 mole percent of 1,2-distearoyl-sn-glycero-3-phosphocholine, approximately 22 percent. mole of dihexadecyl phosphate, about 16 mole percent cholesterol and about 1 mole percent of a targeting agent. Calcitonin is a hormone that regulates the metabolism of bones. Due to the high prevalence of diseases such as osteoporosis, an oral formulation of this hormone is very desirable. Currently, calcitonin can only be given by injection. In one embodiment of the invention that is designed for the delivery of calcitonin, the 1 lipid components selected from the constituents of composition 1 including calcitonin, include about 62 mole percent of 1,2-distearoyl-sn-glycero-3. -phosphocholine, approximately 22 mole percent of; dihexadecyl phosphate, and approximately 16 mole percent cholesterol. , GLP-1 is a peptide that acts both in the liver and in the. pancreas. In the liver, GLP-1 acts to stimulate the accumulation of glycogen during a meal. However, prior art administration methods, in which GLP-1 is administered orally, do! obvious poor bioavailability and reduced efficacy with oral dosing. In one embodiment of the present invention, GLP-1 is associated with a constituent of a composition of the invention, derived from a constituent / GLP-1 construct. The constituent / GLP-1 construct can also include a targeting agent. Preferably the lipid components selected from the constituents of the composition including GLP-1 include about 62 mole percent of 1,2-distearoyl-sn-glycero-3-phosphocholine, about 22 mole percent of dihexadecyl phosphate, and about 16 mole percent cholesterol. Thyroxine, like insulin, is usually not orally bioavailable either. But in one embodiment of the invention, the thyroxine may be associated with a constituent of a composition of the invention forming a constituent / thyroxine construct. Preferably the lipid components selected from the constituents of the composition including thyroxine, include about 62 mole percent of 1,2-distearoyl-sn-glycero-3-phosphocholine, about 22 mole percent of: dihexadecyl phosphate, approximately 16 percent. 100 mole of cholesterol, and about 1 mole percent of Biotin DHPE. Although the invention has been described in terms of specific therapeutic agent / constituent constructs, any of the therapeutic agents described herein may be associated with a constituent of the invention to form a therapeutic agent / constituent construct.

Therapeutic agents covalently linked In certain embodiments of the invention, the therapeutic agent is it can bind covalently to a lipid component of the invention. Without However, normally the covalent binding of the therapeutic agent to the lipid component is not direct, but is mediated by a linker the shape -C (0) (CH2) nSR, wherein an amide, ester or o-bond is formed; thioamide between the therapeutic agent and the linker. Preferably, n is a whole between 1 and 10. Still more preferably n is 1, 2 or 3. When the linker is going to bind to the therapeutic agent, usually R is a group protector, such as -C (0) CH3. Other suitable thiol protecting groups are can be found in Green's Protective Groups in Organic Synthesis, Wuts, et al, 4th edition, 2007.

After the linker binds to the therapeutic agent, the protecting group, R, is removed from the linker to reveal a free thiol group.; i Preferably the protecting group is removed under conditions that do not disturb the now bound therapeutic agent. This thiol can suffer one; Michael's reaction with a lipid component, such as MPB-PE, to form an ether ether. Preferably the MPB-PE lipid component is already! incorporated into a constituent of a compound of the invention, however, the linker can be attached to the MPB-PE prior to its incorporation into a constituent of the invention. The order of the reactions will depend on the ability of the therapeutic agent to tolerate certain reaction conditions. : In the case of proteins that can be denatured at high temperatures, it is preferable to perform the Michael reaction after incorporating MPB-PE into a constituent of the compound of the invention. In one example of a covalent interaction, IgG was covalently linked to a lipid component of a constituent of the invention to form a constituent / IgG construct. IgG is an antibody that is not normally orally bioavailable. In this embodiment of the invention, the lipid components selected to form the; Constituent construction / IgG constituents include about 68 mole percent 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, about 18 mole percent dihexadecyl phosphate, about 9 mole percent cholesterol, and about 3 percent mole percent of MPB-PE. To form the constituents of the invention, 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate and I cholesterol were microfluidized as described hereinbefore, to form constituents; with a maximum size limit between 50 and 60 nanometers. This suspension of constituents was then transferred to a round bottom flask which had been coated with a thin film of MPB-PE. The suspension was heated to approximately 62 ° C, not dropping the temperature to below 60 ° C or exceeding 65 ° C. Then the hot suspension was stirred for 15 minutes until all the MPB-PE had been! incorporated into the constituents of the invention.

IgG was reacted separately with a 10-fold excess of linker precursor I (R = CH3C (0), n = 1), below, to form II. The compound II was then purified using a 2.5 x 25 cm Sephadex G-25 column equilibrated with 8 mM phosphate pH regulator plus 1.0 mM EDTA pH buffer at pH 7.4. Then, the acetyl protecting group in compound II was removed by stirring compound II with 50 mM hydroxylamine hydrochloride in 18 mM sodium phosphate buffer containing 1.0 mM EDTA (pH 7.4) for 2 hours at room temperature. The resulting free thiol III was purified on a 2.5 x 25 cm Sephadex G-25 column, as established for compound II.

Immediately after purification, 200 μ-moles of compound III were mixed with 10 ml of the constituent solution prepared above. The reaction mixture was stirred for 15 minutes, during this time compound III underwent a Michael reaction with the maleimide functionality of the MBP-PE incorporated in the constituents of the invention. The conjugation reaction was stopped, and excess III was removed with the addition of a 50x molar excess of N-ethylmaleimide. Although the above example was described with respect to IgG, it is equally applicable to any therapeutic agent with a basic nitrogen or free hydroxyl group, or other functionalizable group, which is capable of binding to the linker or linker precursor Stability Although the constituent members of a composition of the present invention are formulated in an aqueous medium, the constituent members of the composition do not exhibit long-term stability in water. Specifically, water aids in the hydrolysis of all acyl chains that are present in any of the lipid components of the constituents of the composition. The aqueous environment also allows easy oxidation of any unsaturated acyl chain that is present in any of the lipid components. In a preferred embodiment of the present invention, the constituents of the composition of the present invention can be protected for long-term storage by interaction with a proteoglycan, such as a modified collagen, known generically as dry granulated gelatin. The dried granulated gelatin, when contacted with an aqueous suspension of constituents, reacts with water, stabilizes the constituents and forms a composition of the present invention. The reaction of dry granulated gelatin with an aqueous suspension of constituents of a composition of the present invention results in a semi-solid colloidal gel that protects the constituents from direct interaction with water. All water that is not associated with the Gelatine is slowly evaporated by refrigerated storage from about 2 ° to about 8 ° C. But the water can be removed by means of techniques that include, but are not limited to, freeze-dried and spray-dried. This results in a constituent / gelatin complex "dry" pellet type which is the composition of the invention. In the composition, the constituent elements are partially dehydrated in a reversible manner and are sequestered by the dry gelatin protein lattice. This sequestration is possible by means of structured water, structured lipid and structured gelatin, all interacting by means of hydrogen bonding, ionic bonding, Van der Waal interactions and by hydrophobic binding between the lipid components, water and protein structures, that is, insulin. This shows that gelatin is not acting as an emulsifying or suspending agent. As a result, the "dry" pellet is stable for long-term storage, since water activity has been mitigated. These pellets can be further processed to produce a free-flowing granulate or powder to finally introduce them into a capsule or to form tablets, while maintaining their stability. In oral administration to a patient, the "dry" pellet is hydrated and once again assumes a semi-solid colloidal gel state. By continuing to expose it to the gastric environment, the gel becomes liquid when the gelatin dissolves. Once the gelatin is completely dissolved, the constituent members of the composition of the invention are rehydrated, giving as; result in the formation of a new suspension of constituents in the gastric environment. Then the reconstituted constituents can be absorbed into the portal blood flow. It is important to note that the role of gelatin in this aspect of the invention is that of an active stabilizer of the composition, and not that of an inert filler, as is commonly found in the oral formulations of many other pharmaceutical compositions. That is, the additional use of gelatin as an inert filler is contemplated in addition to the aforementioned use. Although gelatin is used in a preferred embodiment of the invention, other gelatin-type compounds can also be used. Examples of agents that will act as active stabilizers include, but are not limited to, acacia (gum arabic), agar (agar-agar, vegetable gelatin, gelatin, Chinese or Japanese gelatin), alginic acid, sodium alginate (alginic acid; sodium, Algin, Manucol, Norgina, Kelgina), carbomer (carboxypolymethylene), carrageenan, sodium carboxymethylcellulose (Carbosa D, carboxymethyl S, CMC, cellulose gum), cellulose powder (Degussa), hydroxyethyl cellulose (cellulose), 2-hydroxyethyl ether Cellosize, Natrosol), hydroxypropyl cellulose (cellulose, 2-hydroxypropyl ether, Klucel), hydroxypropyl methylcellulose (cellulose, 2-hydroxypropyl methyl ether), meticellulose (cellulose, methyl ether Methocel), povidone (2-pyrrolidinone, 1-ethenyl- homopolymer, polyvinylpyrrolidone), tragacanth (tragacanth gum, sawdust gum, astragalus gum), and xanthan gum (Keltrol). Same as gelatin, and when appropriate, these compounds can also be used as inert fillers.

Formulations A formulation of a composition of the invention and therapeutic agent (with or without the targeting agent) - hereinafter "composition" - for oral administration, can be prepared, packaged or sold in the form of a discrete solid dose unit which includes, but is not limited to, a tablet, a hard or soft capsule, a plain capsule, lozenge or a lozenge, each containing a predetermined amount of the active ingredient. Other formulations suitable for oral administration include, but are not limited to, a powder or granule formulation, aqueous suspensions or emulsions. For example, a tablet comprising the composition of the present invention can be made by compression or molding of the composition, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing, in a suitable device, the composition in a free-flowing form, such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, an active agent of surface, and a dispersing agent. The molded tablets can be made by molding, in a suitable device, the composition, a pharmaceutically acceptable carrier, and finally enough liquid to moisten the mixture.

The pharmaceutically acceptable excipients that are used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate. Known surface active agents include, but are not limited to, sodium lauryl sulfate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. The known granulation and dispersing agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone and hydroxypropyl methylcellulose. Known lubricants include, but are not limited to, magnesium stearate, stearic acid, silica, and talc. The tablets may be uncoated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thus providing a sustained release and absorption of the composition. By way of example, a material such as glyceryl monostearate or glyceryl distearate can be used to coat tablets. Also as an example, the tablets may be coated using the methods described in the U.S. Patents. Nos. 4,256,108; 4,160,452; and 4,265,874 to form release tablets osmotically controlled. The tablets may also comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination thereof to provide a pharmaceutically elegant and palatable preparation. The hard capsules comprising the composition can be made using a physiologically degradable composition, such as gelatin. Said hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, kaolin or acid phthalate of cellulose acetate. The soft gelatine capsules comprising the composition can be made using a physiologically degradable composition, such as gelatin. Liquid formulations of the composition that are suitable for oral administration can be prepared, packaged and sold either in liquid form or in the form of a dry product to be reconstituted with water or any other suitable vehicle before use, subject to stability limitations described above. Liquid suspensions can be prepared using conventional methods to achieve suspension of the constituents in an aqueous vehicle. Aqueous vehicles include, for example, water and isotonic saline. Oilseeds can only be used as long as these solvents are not incompatible with the constituents of the composition of the present invention. Whenever an oil suspension is not incompatible with the constituents of the composition of the present invention, an oil suspension may also comprise a thickening people. The liquid suspensions may also comprise one or more additional ingredients, provided that said ingredients do not break the structures of the constituents of the composition of the invention. Examples of additional ingredients include, but are not limited to, suspending agents, dispersing or wetting agents; emulsifying agents, emollients, preservatives, pH regulators, salts, flavors, coloring agents and sweetening agents. Known suspending agents include, but are not limited to, sorbitol syrup, sodium alginate, polyvinylpyrrolidone, tragacanth gum, acacia gum, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known emulsifying agents include, but are not limited to, acacia. Known preservatives include, but are not limited to, methyl, ethyl or n-propyl-para-hydroxybenzoates, ascorbic acid and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose and saccharin. Powdered and granulated formulations of a pharmaceutical preparation of the invention can be prepared using known methods. Said formulations can be administered directly to a subject, used, by! example, to form tablets, to fill capsules, or to prepare a suspension or aqueous solution with the addition of an aqueous vehicle thereto. Each of these formulations may also comprise one or more of a dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweeteners, flavors or colorants may also be included in these formulations.

Disease treatment methods Diseases, such as diabetes, can be treated by orally administering a compound of the invention, wherein insulin is the associated therapeutic agent. Diabetes can also be treated by orally administering a compound of the invention, wherein insulin is the associated therapeutic agent and wherein another form of insulin is co-administered. Routes of co-administration include, but are not limited to, oral administration, intramuscular injection, inhalation, intravenous injection., intra-arterial injection, as well as any other form of administration. Although the healthcare professional will be able to select the appropriate dose for a given patient, the dose scale that can be administered in a given formulation of a compound of the invention is from about 1 to about 40 units, but can be from 5 to 10. , 15, 20, 25, 30, or 35 units. But a given formulation may contain all or a part of an integer among them, and may exceed 40 units.

Kits The invention also includes a kit comprising a composition of the invention and an instructional material describing the administration of the composition to a mammal. In another embodiment, this kit comprises a composition of the invention, insulin for co-administration, as well as instructional material describing the co-administration procedure. As used herein, an "instructional material" includes a publication, a recording, a diagram, or any other means of expression that can be used to communicate the usefulness of the composition of the invention in the kit, to effect the relief of various diseases or disorders that are cited herein. Optionally or alternatively, the instructional material may describe one or more methods for alleviating diseases or disorders in a mammalian cell or tissue. For example, the instructional material of the kit can be fixed in a container containing the invention, or it can be packaged together with a container containing the invention. Alternatively, the instructional material can be packed separately from the container, with the intention that the instructional material and the compound be used cooperatively by the receiver.

EXPERIMENTAL EXAMPLES The invention will now be described with reference to the following examples. These examples are only provided for the purpose of illustration, in no way should the invention be considered as limited to these examples, but should be considered to encompass any and all variations that become apparent as a result of the teaching of this .

Experiment 1 Administration of compositions not containing a targeting agent A composition whose constituent members were created from a mixture of lipid components comprising approximately 62 mole percent of 1,2-distearoyl-sn-glycero-3-phosphocholine, approximately 22 mole percent dihexadecyl phosphate, approximately 16 mole percent cholesterol, and no targeting agent was prepared according to the microfluidization procedure which is generally described herein. A known portion of the lipid component comprised phospholipid labeled by 14C. After filtration through a 0.2 micron filter, the average constituent size was less than 100 mm measured with the Coulter Sub-micron Particle Size Analyzer.

Then a body weight sample of 10 mg / kg of the composition (containing 85,000 cpm radio-labeling of 14 C) was injected into the duodenum of an anesthetized rat of 230 grams fasting, but otherwise normal. Blood was taken from the portal and femoral veins at 15 and 30 minutes after dosing for counting (figure 2). 30 minutes after dosing the rat was sacrificed and representative samples were taken for blood, liver and spleen analyzes (figure 3). Marked constituents were found, measured by 14C, in both the portal and femoral blood of the rat. Carried blood levels of labeled 1 C constituents were higher than femoral blood levels (Figure 2). 30 minutes after dosing, approximately 15% of the constituents that were injected into the intestine were found in the blood. Approximately 4% of the counts were found in the liver and approximately 1% were found in the spleen. Considering the relative sizes of the liver and spleen, the splenic uptake was much: higher than the uptake of the liver on a weight basis.

Experiment 2 Hepatocin targeting To demonstrate the absorption of the composition in the intestine, a composition comprising insulin and constituents generated from a mixture of lipid components comprising approximately 61 mole percent of 1,2-distearoyl-sn-glycerin was prepared. -3- phosphocholine, approximately 22 mole percent of dihexadecyl phosphate, about 16 mole percent cholesterol, and about 1 mole percent poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic acid)] (where a known portion of the phospholipid component comprised phospholipid labeled by 1 C) , as cited in the general preparation described herein. Before dosing the marked composition to the rats, the rats were subjected to food fasting for 24 hours and water for 4 hours. They were then allowed to drink water from the fasting rats, from a graduated water bottle containing the composition. After 15 minutes the bottle was removed from the cage with drinking water, the amount of water ingested from the drinking bottle was measured, and the amount ingested in the composition was calculated. Samples of the blood were taken from the rats at 15, 30 and 45 minutes and radiolabelling was counted in each sample (Figure 4). After 45 minutes the rats were sacrificed and the livers were counted for the radio-tag (figure 5). As shown in Figure 4, approximately 8% of the: dose ingested was found in the blood of the rats 15 minutes after the water had been removed from the cage. The amount of the constituents in the blood of the rats remained constant between 15 and 45 minutes. The uptake of the liver was approximately 8% to 45 minutes. Splenic uptake at 45 minutes was approximately 1% of the ingested dose (Figure 5). The total absorption was approximately 17% (including blood, liver and spleen).

Experiment 3 Hepatocyte targeting with a composition in mice treated with Aloxan-Streptozotocin The mice that were used in the present experiment were diabetic by administering streptozotocin and alloxan. Then the diabetic animals were divided into two groups. The control group (11 mice) was dosed orally with regular insulin. The experimental group (7 mice) was dosed orally with a composition comprising insulin and constituents generated from a mixture of lipid components comprising approximately 61 mole percent of 1,2-distearoyl-sn-glycero-3-phosphocholine, approximately 22 mole percent dihexadecyl phosphate, approximately 16 mole percent cholesterol, and about 1 mole percent poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyliminodiacetic acid)] (where a known portion of the phospholipid component comprised labeled phospholipid) by 14C). The dosage was made using the water bottle dosing method described in experiment 2. After making them diabetic, the rats of both groups were treated identically for a period of 7 days and were fed with simple food and water simple. After this 7-day period, rats from the control group were treated for an additional experimental period of 7 days with food and regular insulin in drinking water available at 0.1 U / ml. During the same experimental period or 7 days, the experimental group was fed regular food with the composition of the invention available in the water to drink at 0.1 U / ml. At the end of each 7-day period, blood glucose was measured in a blood sample from the tail vein by means of a Beckman Blood Glucose Analyzer. The pharmacological efficacy of the insulin administered orally in the group dosed with the composition described above is shown in Figure 6. The mice that had received the composition had a statistically significant reduction of blood glucose on day seven (p <0.01). compared to mice that had received regular insulin, whose blood glucose had not been altered at all.

EXAMPLE 4 Administration of Serotin in vivo The hepatic action of a composition comprising serotonin and constituents generated from a mixture of lipid components comprising approximately 61 mole percent of 1,2-distearoyl-sn-glycero-3-phosphocholine, approximately 22 mole percent of dihexadecyl phosphate, approximately 16 mole percent cholesterol, and 1 molar percent poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic acid)] acid was demonstrated in a type 2 diabetic dog (truncal vagotomy). The dog was fasted and then anesthetized. They were placed blood sampling catheters in the hepatic veins and portals to enable simultaneous blood sampling. Glucose was infused into the portal system at a rate of 0.5g / kg / hour. Next, the composition described above was administered intraduodenally in a single dose of 30 g / kg body weight. The results are depicted in Figure 7 and demonstrate that serotonin (also referred to as 5-hydroxytryptamine or 5-HT), administered intraduodenally as a composition of the invention is effective at low doses to convert a type 2 diabetic dog to the production of Hepatic glucose to absorption during a portal glucose load.

EXAMPLE 5 In vivo administration of Calcitonin Normal and fasting control rats were given a dose of salmon calcitonin by subcutaneous injection, in such a way that an initial reduction of 10% of calcium in blood was observed. Blood calcium levels were then measured for six hours after the injection. An experimental group of rats was given the same effective dose of calcitonin by oral gavage, in the form of a composition comprising calcitonin and constituents generated from a mixture of lipid components comprising approximately 61 molar percent of 1,2-fold. -distearoyl-sn-glycero-3-phosphocholine, approximately 22 percent mole of dihexadecyl phosphate, and approximately 16 mole percent of cholesterol. The blood calcium levels were followed for six hours (Figure 8). A reduction in blood calcium was observed up to 20% in rats that were not control. This difference was statistically significant (figure 8).

EXAMPLE 6 Clinical Assay with Insulin Targeted in Subjects with Diabetes Mellitus Type 2 Capsules containing a composition of the invention were prepared. The composition comprised insulin as the therapeutic agent, gelatin and constituents generated from a mixture of lipid components comprising approximately 61 mole percent of 1,2-distearoyl-sn-glycero-3-phosphocholine, approximately 22 mole percent of dihexadecyl. phosphate, about 16 mole percent cholesterol and about 1 mole percent sodium btotine-HDPE salt. Each capsule contained 2U of insulin. Six patients with well-characterized type 2 diabetes participated in the controlled study. Patients were maintained on their usual oral type 2 antidiabetic therapy. The study participants were also given placebo capsules or the capsules described above 30 minutes before a meal with 60 grams of carbohydrates during breakfast, lunch and dinner. Blood samples were taken at frequent intervals over a period of 13 hours and the incremental area under the curve (AUC) was calculated for blood glucose values for each subject. At 0.1 U / kg of body weight / food, the same dose that is frequently used with the subcutaneous injection of insulin in a given food, a statistically significant reduction in AUC was observed for each of the three foods. Figure 10 represents the results of the experiment in graphic format.

EXAMPLE 7 Concentration of Insulin The U-500 insulin contains 500 units of nsulin / ml = 0.5 units / 1 μ? Add 3.36 ml of U-500 insulin to 70 ml of constituent suspension in 18 mM phosphate pH regulator @ pH 7.01. (3,360 μ?) * (0.5 units of insulin / μ?) = 1, 680 units of total insulin in 73.36 ml- (1, 680 units of insulin) / (73.36 ml) = 22.9 units of insulin / ml -or- 34.35 units of insulin / 1.5 ml Load insulin for 21 hours; After loading, chromatograph 1.5 ml of sample on a 1.5 cm x 25 cm column with Sepharose CL-6B gel equilibrated with 18 mM phosphate pH regulator @ pH 7.01 0% free insulin recovered from the column; Recovery of 0% of the total insulin load implies that 100% of the total "loaded" insulin is associated with a constituent of the composition. 34.35 units of insulin x 100% = 34.35 units of insulin bound or associated with the constituents of the invention. Figure 11 represents chromatography described above. A trace showing the elution time of free insulin is included for comparison purposes. As can be seen in the chromatogram, insulin is associated with the constituents of the invention and there is no free insulin in the solution. A preservative included with insulin is not associated with the constituents of the composition of the invention and is visible in the chromatogram.

EXAMPLE 8 Oral supply of GLP-1 The rats were fasting during the night. Subsequently, 800 mg of each of aloxane and streptozotocin were dissolved in 40 ml of PBS (pH 7.0, 0.01 M). The fasted rats were then treated immediately with a dose of 0.5 ml IP to induce insulin deficiency. The animals were then stabilized overnight with water and food. Following the stabilization, the rats were fasted overnight to decongest the glycogen from the liver. Subsequently, 1.5 g of glucose / kg of body weight and GLP-1 were administered in the form of a GLP-1 / constituent construct by oral gavage. The constituents were prepared from a mixture of lipid components comprising approximately 61 molar percent of 1, 2-distearoyl-sn-glycero-3-phosphocholine, approximately 22 mole percent dihexadecyl phosphate, and approximately 16 mole percent cholesterol ("associated GLP-1"). In separate experiments, the amount of associated GLP-1 was varied. The glycogen was measured chemically in the liver at 2 hours after dosing. As a control, non-associated GLP-1 was procured in place of the associated GLP-1. In a separate control, GLP-1 was injected intraperitoneally, in a dose similar to that provided by oral gavage. As shown in Table 3 below, substantially improved oral efficacy was observed for the associated GLP-1 in: comparison with non-associated GLP-1.

TABLE 3 * p = 0.05 compared with oral GLP-1 control EXAMPLE 9 Oral IgG Human antibodies of IgG were covalently linked to a constituent of the invention, as previously described herein ("covalent IgG"). Subsequently, eight 250 gram laboratory rats were prepared with intraduodenal catheters for the administration of covalent IgG. After a one-night fast, 5 ug of covalent IgG was infused into the duodenal catheter. The catheter was subsequently washed with 0.5 ml of pH buffer. Blood samples were taken at 15, 30, 60 and 120 minutes to test the plasma concentration of human IgG antibodies by ELISA reaction. In a control experiment, 5 ug free IgG was infused into the duodenal catheter. The catheter was subsequently washed with 0.5 ml of pH buffer. Blood samples were taken at 15, 30, 60 and 120 minutes to test the plasma concentration of human IgG antibodies by ELISA reaction. The results of both studies are shown in Figure 12. As can be seen in Figure 12, the covalent IgG provided improved plasma concentration of human IgG (AUC) compared to free IgG. Similarly, the covalent IgG improved the Tmax - the time for the maximum concentration, and the Cmax - the maximum plasma concentration observed when dosing. The improved efficacy of covalent IgG, compared to free IgG, thus demonstrates the ability of a compound of the invention to improve the oral absorption of very large proteins into the systemic circulation.

EXAMPLE 10 Oral Thyroxine It is known that thyroxine decreases cholesterol and triglyceride levels in blood. However, at the doses required to treat high cholesterol, triglyceride, and thyroxine, thyroxine causes hyperthyroidism as an undesired side effect. The objective of this study was to demonstrate that targeted and orally administered thyroxine, associated with a compound of the invention, would act in the liver with the result of lowering blood lipids without inducing unwanted hyperthyroidism. Normal laboratory mice, under high-calorie diets, were administered low oral doses (0.2 to 1.0 pg) of thyroxine in the form of a composition comprising thyroxine and constituents generated from of a mixture of lipid components comprising about 61 mole percent of 1,2-distearoyl-sn-glycero-3-phosphocholine, about 22 mole percent dihexadecyl phosphate, about 16 mole percent cholesterol, and about 1 percent molar of the sodium salt of biotin-HDPE, a hepatic targeting agent. The mice were dosed, in groups of 4, daily by feeding with oral gavage for one week in a dose response study. Blood cholesterol and triglycerides were measured after one week of treatment. The baseline values for cholesterol and triglycerides for all groups were similar. The responses to the doses, shown in Figure 13, demonstrate the efficacy of orally administered hepatic targeting thyroxine, associated with a composition of the invention. The blood levels of thyroid hormone did not increase with the dosage of oral thyroxine targeting ^ hepatic, demonstrating the safety of the product. Other published studies (Erion, M., et al., PNAS, Sept. 25, 2007, Vol. 104, # 39, pp. 15490-15495) with hepatic targeting toxin analogues required doses at least 10 times higher than the those described herein to obtain similar reductions of cholesterol and triglycerides in blood.

EXAMPLE 11 Oral interferon A composition comprising interferon-a was prepared as the therapeutic agent and constituents generated from a mixture of lipid components comprising approximately 61 molar percent of 1, 2-distearoyl-sn-glycero-3-phosphocholine, approximately 22 mole percent of dihexadecyl phosphate, approximately 16 mole percent of cholesterol, and about 1 mole percent of the biotin-HDPE sodium salt. Six patients with hepatitis C, genotype 3, were treated with an aqueous suspension of the composition described above and ribivirine daily for 8 weeks. The dose of interferon-a in the aqueous suspension of the composition was 60,000 units / day. Viral loads were measured by hepatitis C at the beginning of the study, then at weeks 1, 2, 4 and 8. See Figure 14. The data demonstrate the ability of the aqueous suspension of a composition of the invention to decrease the load. viral with a minimum dose of interferon. Side effects were minimized in the same way. The disclosures of each and all of the patents, patent applications, and publication cited herein are hereby incorporated by reference in their entirety. Although this invention has been described with reference specific embodiments, it is evident that other embodiments and variations of% this invention can be devised by other experts in the art without departing from the true spirit and scope of the invention. It is intended that the appended claims be construed so as to include all such equivalent modalities and variations.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - An orally bioavailable composition comprising gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment, and lipid particle, wherein said lipid particle comprises at least one lipid component and said liposome or liposome fragment comprises at least two lipid components, said composition further comprising at least one therapeutic or diagnostic agent- and, optionally, at least one targeting agent, wherein said gelatin actively interacts reversibly with one or more of said constituents. 2. The composition according to claim 1, further characterized in that said lipid components are selected from the group consisting of MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl- sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, J, 2- dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine; 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, -N- (succinyl) ,, 1,2-dipalmitoyl-sn-glycero-3- [phospho-rac- (1-glycerol)] (sodium salt) , and triethylammonium phosphate 2,3-diacetoxypropyl 2- (5 - ((3aS, 6aR) -2-oxohexahydro-1 H -thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl. 3. - The composition according to claim 2, further characterized in that said therapeutic agent is selected from the group consisting of insulin, interferon, erythropoietin, parathyroid hormone, calcitonin, serotonin, rituximab, -trastuzumab, uricase, tissue plasminogen activator, thymoglobin, a vaccine, heparin or a heparin analogue, anitrombin III, filgrastin, pramilitide acetate, exanatide, epifibatide, antivenins, IgQ, IgM, HGH, thyroxine, GLP: 1, Blood coagulation factors VII and VIII, a monoclonal antibody, and glycolipids that act as therapeutic agents. 4. The composition according to claim 3, further characterized in that the therapeutic agent is insulin. 5. The composition according to claim 3, further characterized in that the targeting agent comprises a targeting agent derived from metal or a targeting agent derived from biotin. 6. - The composition according to claim 5 characterized further in that said targeting agent derived from metal comprises a metal and at least one complexing agent, wherein the metal in said targeting agent derived from metal is selected from the group consisting of a transition metal, an inner transition metal and a neighbor of the transition metals; and said at least one complexing agent is selected from the group consisting of: N - (- 2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid; N- acid (2,6- diethylphenylcarbamoylmethyl) iminodiacetic; N- (2,6-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (4-isopropylphenylcarbamoylmethyl) iminodiacetic acid; N- (4-butylphenylcarbamoylmethyl) iminodiacetic acid; N- (2,3-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (2,4-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (2,5-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (3,4-dimethylphenylcarbamoylmethyl) iminodiacetic acid; N- (3,5-dimethylphenylcarbamoylmethyl) acid. iminodiacetic; N- (3-butylphenylcarbamoylmethyl) iminodiacetic acid; N- (2-butylphenylcarbamoylmethyl) -iminodiacetic acid; N- (4-butylphenylcarbamoylmethyl tertiary) iminodiacetic acid; N- (3-butoxyphenylcarbamoylmethyl) iminodiacetic acid; N- (2-hexyloxyphenylcarbamoylmethyl) iminodiacetic acid; acid N- (4-hexyloxyphenylcarbamoylmethyl) iminodiacetic; aminopyrrole iminodiacetic acid; N- (3-bromo-2,4,6-trimethylphenylcarbamoylmethyl) iminodiacetic acid; Benzimidazolmethyl iminodiacetic acid; N- (3-cyano-4,5-dimethyl-2-pyrrilcarbamoylmethyl) iminodiacetic acid; N- (3-cyano-4-methyl-5-benzyl-2-: pyrrilcarbamoylmethyl) iminodiacetic acid; and N- (3-cyano-4-methyl-2-pyrrilcarbamoylmethyl) iminodiacetic acid. 7. The composition according to claim 6, further characterized in that said metal is chromium. 8. The composition according to claim 5, further characterized in that said targeting agent derived from metal is poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic acid)] acid. 9. The composition according to claim 5, further characterized in that said targeting agent is a targeting agent derived from biotin selected from the group consisting of N-hydroxysuccinimide (NHS) biotin; sulfo-NHS-biotin; N-hydroxysuccinimide long chain biotin; long chain sulfo-N-hydroxysuccinimide biotin; D-biotin; biocitin; sulfo-N-hydroxysuccinimide-S-S-biotin; biotin-BMCC; biotin-HPDP; iodoacetyl-LC-biotin; biotin hydrazide; biotin-LC-hydrazide; biocytin hydrazide; biotin cadaverine; carboxybiotin; photobiotin; p-aminobenzyl biocytin trifluoroacetate; p-diazobenzoyl biocytin; Biotin DHPE; Biotin-X-DHPE; 12 - ("(biotinyl) amino) dodecanoic acid, 12 - ((biotinyl) amino) dodecanoic acid succinimidyl ester, S-biotinyl homocysteine, biocytin-X, biocytin x-hydrazide, biotinyethylene diamine, biotin-XL, biotin-X -ethylenediamine, biotin-XX hydrazide, biotin-XX-SE, biotin-XX, SSE, biotin-X-cadaverine, a- (t-BOC) biocytin, N- (biotinyl) -N '- (iodoacetyl) ethylenediamine, DNP -X-biocitin-X-SE, biotin-Xhidrazide, norbiotinamine hydrochloride, 3- (N-maleimidylpropionyl) biocytin, ARP, biotin-l-sulfoxide, biotin methyl ester, biotin-maleimide, biotin-poly (ethylene glycol) ) amine, sodium salt of (+) 'biotin-4-amidobenzoic acid, biotin 2-N, -acetylamino-2-deoxy-D-glucopyranoside, biotin-aDN-acetyl neuraminide, biotin-aL-fucoside, biotin lacto- N-bioside, biotin-Lewis-A trisaccharide, biotin-Lewis-Y tetrasaccharide, biotin-aD-mannopyranoside, biotin 6-O-phospho-aD-mannopyranoside, and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine- N- (biotinyl), iminobiotin derivatives of the s compounds mentioned above, and mixtures thereof. 10. The composition according to claim 6, further characterized in that said targeting agent is poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethylinodiadiacetic)] acid and said therapeutic agent is insulin. 1. The composition according to claim 9, further characterized in that said targeting agent is DHPE or biotin-X-DHPE and said therapeutic agent is insulin. 12. - A method for making an orally bioavailable composition comprising gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment, and a particle, wherein said liposome, liposome fragment, and particle are generated from of a mixture of lipid components, said composition further comprises at least one therapeutic agent or diagnostic agent, and optionally at least one targeting agent, wherein said gelatin actively interacts reversibly with one or more of said constituents, said method comprises steps of: a. mixing said lipid components and, optionally, said at least one targeting agent in aqueous media to form a first mixture; b. adding said therapeutic or diagnostic agent to said first mixture to form a second mixture; c. adding said second mixture to the gelatin to form a mixture associated with the gelatin; and d. drying said mixture associated with the gelatin. 13. - The method according to claim 12, further characterized in that: a. said lipid components are selected from the group consisting of MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn- glycero-3-phosphocholine, cholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate. 1, 2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (succinyl), 1, 2-dipalmitoyl-sn-glycero-3- [phospho-rac- (1-glycerol)] (sodium salt), and triethylammonium phosphate 2,3-diacetoxypropyl 2- (5 - ((3aS, 6aR) - 2-oxohexahydro-1 H-thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl; b. when present, said optional targeting agent is a targeting agent derived from metal or a targeting agent derived from biotin; and c. said therapeutic agent is selected from the group consisting of insulin, interferon, erythropoietin, parathyroid hormone, calcitonin, serotonin, rituximab, trastuzumab, uricase, tissue plasminogen activator, thymoglobin, a vaccine, heparin or a heparin analog, - anitrombin III, filgrastin, pramilitide acetate, exanatide, epifibatide, antivenins, IgG, IgM, HG, H, thyroxine, -GLP-1, Factors VII and VIII of blood coagulation, a monoclonal antibody, and glycolipids that act as therapeutic agents. 14. - The method according to claim 13, further characterized in that said targeting agent derived from metal is poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic acid)] acid. 15. - The method according to claim 13, further characterized in that said targeting agent derived from biotin is selected from the group consisting of DHPE and biotin-X-DHPE. 16. - The method according to claim 13, further characterized in that said therapeutic agent is insulin. 17. The use of an orally bioavailable composition comprising gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment and lipid particle, wherein said "lipid particle comprises at least one lipid component and said Liposome or liposome fragment comprises at least two lipid components, in the manufacture of a medicament for treating a disease in a human, wherein the medicament further comprises at least one therapeutic agent and, optionally, at least one targeting agent , wherein said gelatin interacts interactively in a reversible manner with one or more of said constituents ^ 18. - Use as claimed in claim 17, wherein said disease is diabetes 19. - Use as claimed in claim 18, wherein said lipid components are selected from the group consisting of MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, oleate cholesterol , dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn- glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphatide, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, l ^ -dipalmitoyl-sn-glycero-S-phosphoethanolamine-N-isuccinyl ), 1. 2- d -palmitoyl-sn-glycero-3- [phospho-rac- (1-glycerol)] (sodium salt), and triethylammonium 2. 3- diacetoxypropyl 2- (5 - ((3aS, 6aR) -2-oxohexahydro-1 H -thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl phosphate; said at least one or more therapeutic agents is insulin; and when present, said optional targeting agent is a targeting agent derived from metal or a targeting agent derived from biotin. 20. The use as claimed in claim 19, wherein said targeting agent is not optional and is poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic acid)], biotin DHPE, or biotin- X-DHPE. 21. The composition according to claim 1, further characterized in that said lipid components are 1,2 distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate, and cholesterol; said targeting agent is not optional and is poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic acid)]; and said therapeutic agent is insulin. 22. The composition according to claim 1, further characterized in that said lipid components are 1, 2 distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate, and cholesterol; said targeting agent is not optional and is biotin-X-DHPE or biotin DHPE; and therapeutic agent is insulin. 23. - The use as claimed in claim 17, wherein said lipid components are 1,2-distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate, and cholesterol; said targeting agent is not optional and is poly [Cr-bis (N-2,6-diisopropylphenylcarbamoylmethyl iminodiacetic acid)]; and said therapeutic agent is insulin. 24. The use as claimed in claim 17, wherein said lipid components are 1,2-distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate, and cholesterol; said targeting agent is not optional and is biotin-X-DHPE or biotin DHPE; and therapeutic agent is insulin. 25. - A composition of the invention made by a method comprising the steps of: a. mixing at least three lipid components and, optionally, at least one targeting agent in aqueous media to form a first mixture, wherein said components are selected from the group consisting of MPB-PE, 1, 2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, cholesterol oleate, phosphate of dihexadecyl, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl -sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (succinyl), 1,2-dipalmitoyl-sn-glycero-3- [phospho-rac- (1-glycerol )] (sodium salt), and triethylammonium phosphate 2,3-diacetoxypropyl 2- (5 - ((3aS, 6aR) -2-oxohexahydro-1 H -thieno [3,4-d] imidazol-4-yl) pentanamide) ethyl; b. subjecting said mixture to homogenization to form a mixture of liposomes, liposome fragments and particles; c. adding a therapeutic or diagnostic agent to said mixture of liposomes, liposome fragments and particles to create a second mixture; d. adding said second mixture to the gelatin to form a mixture associated with the gelatin; and e. drying said mixture associated with the gelatin. 26. - The use of an orally-bioavailable composition comprising gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment, and lipid particle, wherein said lipid particle comprises at least one component lipid and said liposome or liposome fragment comprises at least two lipid components, in the manufacture of a medicament for treating diabetes in a human, wherein said medicament further comprises insulin and, optionally, at least one targeting agent, wherein said gelatin interacts actively reversibly with one or more of said constituents; and, wherein said medicament is adapted to be co-administrable with insulin. 27. - A kit that includes: a. an orally bioavailable composition comprising gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment, and lipid particle, wherein said lipid particle comprises at least one lipid component and said liposome or The liposome fragment comprises at least two lipid components, said composition further comprising at least one therapeutic or diagnostic agent and, optionally, at least one targeting agent, wherein said gelatin interacts actively reversibly with one or more of said constituents; and b. instructional material for the administration of said composition to a human. 28. The kit according to claim 27, further characterized in that it additionally comprises insulin for co-administration with said composition to said human. 29. An orally bioavailable composition comprising gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment, and lipid particle, wherein said lipid particle comprises at least one lipid component and said liposome or fragment thereof. The liposome comprises at least two lipid components, said composition further comprising at least one targeting agent derived from biotin, wherein said gelatin actively interacts reversibly with one or more of said constituents. 30. The composition according to claim 29, further characterized in that said lipid components are selected from the group consisting of MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn -glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, cholesterol oleate, dihexadecyl phosphate, l-distearoyl-sn- glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-diministoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (succinyl), 1,2-dipalmitoyl-sn-glycero-3- [phospho-rac- (1-glycerol)] (sodium salt), and phosphate triethylammonium 2,3-diacetoxypropyl 2- (5 - ((3aS, 6aR) -2-oxohexahydro-1 H -thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl. 31. The composition according to claim 30, further characterized in that said targeting agent derived from biotin is selected from the group consisting of N-hydroxysuccinimide (NHS) biotin; sulfo-NHS-biotin; N-hydroxysuccinimide long chain biotin; long chain sulfo-N-hydroxysuccinimide biotin; D-biotin; biocitin; sulfo-N-hydroxysuccinimide-S-S-biotin; biotin-BMCG; biotin-HPDP; iodoacetyl-LC-biotin; biotin hydrazide; biotin-LC-hydrazide; biocytin hydrazide; biotin cadaverine; carboxybiotin; photobiotin; p-aminobenzoyl biocytin trifluoroacetate-p-diazobenzoyl biocytin; Biotin DHPE; Biotin-X-DHPE; 12 - ((biotinyl) amino) dodecanoic acid; succinimidyl ester of 12 - ((biotinyl) amino) dodecanoic acid; S-biotinyl homocysteine; biocitin-X '; biocitin x-hydrazide; biotinyethylene diniarnine; biotin-XL; biotin-X-ethylene diamine; biotin-XX hydrazide; biotin-XX-SE; biotin-XX; SSE; biotin-X-cadaverine; a- (t-BOC) biocytin; N- (biotinyl) -N '- (iodoacetyl) ethylenediamine; DNP-X-biocitin-X-SE; biotin-X-hydrazide; Norbiotinamine hydrochloride; 3- (N-maleimidylpropionyl) biocytin; ARP; biotin-l-sulfoxide; biotin methyl ester; biotin-maleimide; biotin-poly (ethylene glycol) amine; sodium salt of (+) biotin-4-amidobenzoic acid; biotin 2-N-acetylamino-2-deoxy-3-D-glucopyranoside; biotin-a-D-N-acetyl neuraminide; biotin-a-L-fucoside; lacto-N-bioside biotin; biotin-Lewis-A trisaccharide; biotin-Lewis-Y tetrasaccharide; Biotin-a-D-mannopyranoside; biotin 6-O-phospho-a-D-mannopyranoside; and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (biotinyl), iminobiotin derivatives of the compounds mentioned above, and mixtures thereof. 32. - The composition according to claim 31, further characterized in that said targeting agent derived from biotin is biotin DHPE or biotin-X-DHPE. 33. - A method for making an orally bioavailable composition comprising gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment, and a lipid particle, wherein said liposome, liposome fragment, and lipid particle are generated at From a mixture of lipid components, said composition further comprises at least one targeting agent derived from biotin, wherein said gelatin actively interacts reversibly with one or more of said constituents, said method comprising the steps of: mixing said lipid components and said at least one targeting agent derived from biotin in aqueous media to form a mixture; adding said mixture to gelatin to form a mixture associated with gelatin; and drying said mixture associated with gelatin. 34. - The method according to claim 33, further characterized in that: said lipid components are selected from the group consisting of MPB-PE, 1, 2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine , cholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmito-1-sn-glycero-3-phosphate, 1, 2- dimyristoyl-sn-glycero-3-phosphate, l ^ -distearoyl-sn-glycero-S-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- (succinyl), 1,2-dipalmitoyl-sn -glycero-3- [phospho-rac- (1-glycerol)] (sodium salt, and triethylammonium phosphate 2,3-diacetoxypropyl 2- (5 - ((3aS, 6aR) -2-oxohexahydro-1 H-thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl The method according to claim 34, further characterized in that said derivatized targeting agent is selected from the group consisting of biotin DHPE and biotin. X-DHPE.